Original Articles Journal of Korean Epilepsy Society Journal of Korean Epilepsy Society 13(2):58-64, 2009 ISSN 1226-6965 Received November 28, 2009 Accepted December 27, 2009 울산대학교의과대학서울아산병원소아청소년과 Study of Clinical Course of Epilepsy in Children with Tuberous Sclerosis Complex Eun Hye Lee, MD, Min Hee Jeong, MD, and Tae-Sung Ko, MD Department of Pediatrics, Asan Medical Center, Ulsan University College of Medicine, Seoul, Korea Purpose: The aim of this study is to investigate the incidence, clinical features and outcome in pediatric tuberous sclerosis complex (TSC) patients with epilepsy. Methods: Fifty seven of 74 patients (77.0%) were included in the study, who were diagnosed with epilepsy associated with TSC from 1991 to 2008. Clinical data were obtained from medical records retrospectively. Results: Of the 57 patients, initial seizure types were infantile spasms (n=25, 43.8%), complex partial seizure (n=24, 42.1%), generalized tonic seizure (n=5, 8.7%), simple partial seizure (n=2, 3.4%), and atonic seizure (n=1, 1.7%), respectively. Seventeen patients (29.8%) had changes of their seizure types during the clinical course. Excluding the five patients with insufficient data, 52 patients were treated with antiepileptic drugs and four of them underwent epilepsy surgery. Twenty-six of 52 patients (50.0%) with medical treatment and two patients (50.0%) with epilepsy surgery became seizure free. Among the patients with infantile spasms, vigabatrin induced seizure freedom in 13 of 14 patients (92.8%) within four weeks, and five of them maintained seizure remission with vigabatrin monotherapy. Conclusions: Half of epileptic patients showed good responses to medical treatment, especially vigabatrin for infantile spasms. Epilepsy surgery can be treatment option for selected patients. Keywords: Tuberous sclerosis; Epilepsy; Infantile spasms; Vigabatrin 서론 결정성경화증 (Tuberous sclerosis complex) 은상염색체우성으로유전되는신경피부증후군의대표적인질환으로, 뇌, 눈, 심장, 신장, 폐, 피부등여러장기에발생하는선천성과오종을특징으로한다. 1-5 병리학적으로는신경세포의이주, 분화, 증식의이상으로중추신경계에특징적인피질결절 (cortical tuber) 과뇌실막하소결절 (subependymal nodule) 이관찰되고임상적으로는간질발작, 지적장애, 자폐증과같은다양한신경학적이상을나타낸다. 4 그중에서도발작은가 장흔한증상으로, 결절성경화증환자의 84~92% 가일생동안발작을경험하는것으로알려져있다. 5 간질발작은주로생후 1년내에시작하여결정성경화증의첫임상양상으로발현하는경우가많으며, 초기에는영아연축, 부분발작등으로나타나다가후기에는빈도가증가하며약물치료에잘반응하지않아난치성간질의주요원인이된다. 최근연구들에의하면국소적인간질유발성병변 (epileptogenic area) 이있는경우수술적치료를통해좋은결과를얻을수있는데, 뇌자기공명영상과단일광자방출단층촬영, 양전자방출촬영등의다양한수술전검사들의발달로난치성간질이있는 Address for correspondence: Tae-Sung Ko, MD Department of Pediatrics, Asan Medical Center, Ulsan University, College of Medicine #388-1 Pungnap-dong, Songpa-gu, Seoul 138-736, Korea Tel: +82-2-3010-3386, Fax: +82-2-473-3725, E-mail: tsko@amc.seoul.kr 58
결절성경화증환자의수술적치료의가능성이높아졌다. 6,7 국내에서결절성경화증의전반적인임상양상이나증례보고는몇있으나, 결절성경화증에서의간질발작의임상경과와발작형태의변화에대해서는보고된바가없다. 저자들은결절성경화증소아에동반되는간질발작의유형과임상경과및예후에대해조사해보고자본연구를시행하였다. 대상과방법 1991년 1월부터 2008년 12월까지서울아산병원소아청소년과에서결절성경화증으로진단받은환자 74명을대상으로하였다. 결절성경화증의진단기준은 Roach 등 8 의기준을바탕으로하였으며간질의진단은유발요인없이 2회이상발작을경험한환자로정의하였다. 후향적의무기록조사를통해 ILAE (International League Against Epilepsy) 분류에따른간질발작의형태를구분하고, 발작의발생나이, 시간경과에따른발작형태의변화, 예후에대해조사하였다. 중도탈락한환자를제외한후, 약물치료의전반적인효과에대해조사하였으며, 임상적인특징이발작소실률과관련이있는지분석하였다. 또한영아연축이동반된환자중본원에서진단시부터치료를받았던환자에대해서는항경련제를투여하기전과비교하여간질발작의횟수가어떻게변하였는지를 3단계로 (<50% 감소, 50% 감소, 발작소실 ) 로나누어분석하여각약물에대한반응을알아보았다. Vigabatrin을투여한군과 vigabatrin 외의약제로치료한군을나누어 Fisher s exact test를이용하여두군간에발작소실률에유의한차이가있는지검증하였다. 수술적치료를받은환자에서는뇌자기공명영상소견과발작간기및발작기뇌파, 수술후결과에대해조사하여수술후예후에영향을미치는인자에대해분석하고자하였다. 결과 1. 간질발작의유형및변화양상 전체환자 74명 ( 남자 44명 ; 여자 30명 ) 중, 한번이상발작을경험한환자는 61명 (82.4%) 으로이중 57명 (77.0%) 의환자가간질로진단받았다. 간질발작의발병연령은평균 11.2 개월 ( 생후 4일 ~72개월 ) 이었고, 12개월이전에발생한경우가 44예 (77.1%), 12개월후에발생한경우가 13예 (22.8%) 였다. 최초간질발작의유형은 12개월이전에발생한환자들에서는영아연축이 25예로가장많았고, 복합부분발작이 13예, 전신강직성발작이 4예, 탈력발작 1예, 단순부분발작 1예순이었다. 12개월후에발생한환자들에서는복합부분발작이 11예, 전신강직성발작과단순부분발작이각 1예씩관찰되었다. 총 57예중 17예 (29.8%) 에서시간에따른발작형태의변화가관찰되었다. 이중 15예는 12개월이전에간질발작이발생한환자들이었다. 처음영아연축을보였던환자중 9예는 후에레녹스가스토증후군 3예, 전신발작 3예, 복합부분발작 3예로발작형태가변하였으며, 변화시기는 20개월에서 34개월까지다양하였다. 신생아기에부분발작을보이다가 4개월, 5개월, 8개월에영아연축으로발작형태가변한경우도 3예에서관찰되었다. 이중 8개월에영아연축을보인환자는 9개월부터는부분발작양상으로한번더발작유형이변화하였다. 4예에서는복합부분발작에서전신발작으로변화하였으며, 탈력발작 1예는복합부분발작으로발작형태의변화를보였다 (Table 1). 2. 약물치료에대한효과 간질이동반된 57예중추적관찰중도탈락한 5예를제외한 52예에서약물치료후의반응을조사하였다. 평균 67.0개월추적관찰후약물치료만으로발작이소실된환자는 50.0% 인 26명이었다. 10예 (19.2%) 에서는한달에한번이상, 5예 (9.6%) 에서는 1주일에한번이상간질발작이관찰되어 Table 1. Clinical course of seizure types according to onset age Onset age Seizure type 12 m >12 m Total No change group 29 11 40 (70.1%) IS 16 0 16 CPS 8 9 17 GTS 4 1 5 SPS 1 1 2 Change group 15 2 17 (29.8%) IS LGS 3 0 3 IS CPS 3 0 3 IS GTS 3 0 3 CPS IS 3 0 3 CPS GTCS 2 2 4 Atonic seizure CPS 1 0 1 Total 44 (77.1%) 13 (22.8%) 57 (100%) M, months; IS, infantile spasms; CPS, complex partial seizure; GTS, generalized tonic seizure; SPS, simple partial seizure; LGS, Lennox-Gastaut syndrome; GTCS, generalized tonic clonic seizure. Journal of Korean Epilepsy Society Vol. 13 No. 2, 2009 59
약물치료에불완전한반응을보였으며, 다양한약물치료에도불구하고매일한번이상의발작을경험하는경우도 11예 (21.1%) 에서관찰되었다 (Table 2). 약물치료에반응하지않는환자중에서 4예에서는간질수술을시행하였다. 발작의소실률은발작이 12개월이전에발병한경우, 임상경과중영아연축이있었던경우, 발작형태의변화가없었던경우에서다소높게나타났지만, 의미있는차이는보이지않았다 (Table 3). 영아연축으로간질이발현했던환자 25예중에서본원에서처음부터약물치료를시작하였던 19예에대해서는따로분석을실시하였다. 19예중 12예에서 vigabatrin 이첫약물로투여되었는데, 11예에서 4주이내에발작이소실되었다. 5예에서는경련발작의소실이잘유지되어약물을중단하거나 (n=1), zonisamide 로성공적으로약물을변경하였고 (n=4), 나머지 5예에서는발작이재발하여다른약물을필요로하였 다. 초기에 vigabatrin 외에다른약물을투여하였던환자는 7 명이었으며이중 2예에서두번째약물로 vigabatrin 을투여하여발작이소실되었다 (Figure 1). 영아연축이동반된환자에게 vigabatrin 외에투여된약물은 zonisamide, clobazam, levetiracetam, topiramate 등이었으며, 총 37건의약물처방을조사하여각약물의효과를알아보았다. vigabatrin 은총 14예에서투여되었는데이중 13예 (92.8%) 에서발작이소실되었으며, zonisamide는 6예중 4예, clobazam은 5예중 3예, levetiracetam은 4예중 3예에서발작소실을보였다. 숫자는적었지만 valproic acid가투여된 2예는모두발작이잘조절되었다 (Figure 2). Vigabatrin을투여한군과그외의약제로치료한군에서발작소실률을비교하였을때, vigabatrin군에서발작소실률이더높은경향이있었으나통계적으로유의하지는않았다 (p=0.056). Table 2. Seizure outcomes of antiepileptic drug treatment Seizure frequency Seizure type free 1/m 1/w 1/d F/U loss Total No change group 40 (70.1%) IS 8 1 0 4 3 16 CPS 9 5 2 1 17 GTS 0 2 0 2 1 5 SPS 1 0 0 0 1 2 Change group 17 (29.8%) IS LGS 2 0 0 1 3 IS CPS 1 0 2 0 3 IS GTS 2 0 1 0 3 CPS IS 2 0 0 1 3 CPS GTCS 0 2 0 2 4 Atonic seizure CPS 1 0 0 0 1 Total 26 10 5 11 5 57 (100%) M, month; w, week; D, day; F/U, follow-up; IS, infantile spasms; CPS, complex partial seizure; GTS, generalized tonic seizure; SPS, simple partial seizure; LGS, Lennox-Gastaut syndrome; GTCS, generalized tonic clonic seizure. Table 3. Seizure outcomes by clinical characteristics Clinical characteristics Uncontrolled Total Onset age 12 m 21 (53.8%) 18 (46.1%) 39 >12 m 6 (46.1%) 7 (53.8%) 13 Infantile spasms during the clinical course Yes 15 (60.0%) 10 (40.0%) 25 No 12 (44.4%) 15 (55.5%) 27 Change of seizure types Yes 8 (47.0%) 9 (52.9%) 17 No 18 (51.4%) 17 (48.5%) 35 60
F/U loss N=1 Total N=19 VGB N=12 N=11 Uncontrolled N=1 D/C VGB N=1 Switch to ZNS N=4 Second AED N=5 Third AED N=3 Fourth AED Other AEDs N=7 Uncontrolled N=4 N=3 VGB Second AED Third AED Figure 1. Clinical courses of infantile spasms with TSC. AED, antiepileptic drug; VGB, vigabatrin; F/U, follow up; ZNS, zonisamide. 14 12 10 seizure free seizure reduction 50% seizure reduction< 50% 8 6 4 2 0 CLB LEV LTG OXC TPM VGB VPA ZNS Antiepileptic drugs Figure 2. The effect of various antiepileptic drugs on seizure reduction in infantile spasms with TSC. CLB, clobazam; LEV, levetiracetam; LTG, lamotrigine; OXC, oxcarbazepine; TPM, topiramate; VGB, vigabatrin; VPA, valproic acid; ZNS, zonisamide. Figure 3. EEG of patient 1 shows very frequent spike and slow wave discharges from right fronto-centro-temporal areas. Also synchronous discharges from left fronto-centro-temporal area are noticed. This record is suggestive of partial epilepsy originating from right fronto-centro-temporal area. 3. 수술적치료에대한효과약물치료에반응이없는환자중 4예에서간질수술이시행되었다. 뇌자기공명영상에서간질유발성병변이하나이고뇌파에서국소화가잘되었던증례 1(Figure 3, 4) 과증례 3에서는병변절제술을시행하여간질발작이소실되었다. 증례 2는뇌자기공명영상에서여러개의병변이있었고, 발작간기뇌파와발작기뇌파에서병변이국소화되지않아서침습성검사및대뇌피질자극검사까지시행하였고, 오른쪽전두엽피질절제와측두엽결절절제, 뇌량절제술후, 70~80% 의간질발작감소를보였으나현재는발작이다시악화된상태이다. 증례 4는좌측측두엽과후두엽에다수의피질결절이있는환자로, 발작기뇌파에서편측화가되지않아침습성검사와양전자방출촬영시행후좌측측두엽간질로진단하였다. 좌측측두엽절제술후발작이소실되어 약물을완전히중단하였으나, 수술후 4년뒤에재발하여다시약물치료중이다 (Table 4). 고찰 결절성경화증환자에서간질의유병률은상당히높아서, 80~90% 정도로보고되고있다. 5 간질발작은대부분 1세이전에발생하며시간에따라다양한형태를보이는것이특징이다. 1,4 본연구에서간질의유병률은 77.0% 였으며 77.1% 의환자에서 1세이전에간질발작이시작되었다. 결절성경화증에서발작의형태는보고마다그빈도에차이가있어서, Gomez 등 5 의보고에서는영아연축 37%, 전신발작 27%, 단순부분발작 24% 순이었으며, 국내김등 9 의보고에서는부분발작 33.3%, 전신발작 33.3%, 영아연축 24.6% 였다. 본연구에서초기발작형태는영아연축이 43.8% 로가장많았고 Journal of Korean Epilepsy Society Vol. 13 No. 2, 2009 61
복합부분발작 42.1%, 전신간대발작 8.7% 순이었는데, 처음에영아연축을보인환자의 36.0% 에서부분발작, 전신발작, 레녹스가스토증후군등다양한양상으로발작형태의변화를보였다. 특히 12개월이전에발병한환자들이 12 개월후에발병한환자들보다발작형태의변화를더많이나타내었는데, 이들에서영아연축이다수포함되어있기때문인것으로생각된다. 일본의한연구에서는 38명의결절성경화증환자중, 11예의영아연축에서부분발작으로, 6예의영아연축에서레녹스가스토증후군으로발작의형태가변화한것이보고된바있다. 10 Curatolo 1 에의하면결절성경화 A Figure 4. (A) Axial T2W images of patient 1 shows large focal cortical dysplasia (35 23 mm) with probable calcificaiton in right frontal lobe. (B) Axial T2W image shows postoperative change of patient 1. B 증에동반된영아연축에서처음에는뇌의두정엽이나후두엽에서발작파가나타나다가 2년후에는전두엽에서양측성동기화양상의극서파양상을보이는새로운발작파가나타나는데, 이러한뇌파의변화로결절성경화증에서나타나는발작형태의변화를일부설명할수있으나정확한기전이나예후인자에대해서는아직까지확실히알려져있지않다. 결절성경화증에동반된간질발작에서의약물치료는발작의형태에따라적용된다. 본연구에서는약물치료만으로치료한 52명의환자중 26예에서발작이소실되어전체적으로 50.0% 의반응을보였으며, 발병연령이 12개월이전인경우와임상경과중영아연축을보였던환자들, 또한발작형태가변하지않은환자들에서다소발작소실률이높았으나, 의미있는차이를보이지는않았다. 문헌상에는 11,12 영아연축으로처음발현한환자들을장기간추적관찰했을때 30% 에서만발작소실상태를유지한다고하는데, 본연구도더장기간추적관찰이필요할것으로생각된다. 영아연축의치료에는 vigabatrin 과 ACTH 가효과가있는것으로잘알려져있다. 특히 vigabatrin 은다른원인으로인한영아연축보다훨씬더우수한효과를내는것이여러연구에서입증되었다. 13-16 본연구에서도영아연축환자들에서 vigabatrin 이비교적우수한효과를나타내어이전의보고들과일치하는결과를보였다. 어린나이에간질발작이지속되면인지기능의저하를초래할뿐아니라행동장애, 자폐 Table 4. Summary of cases with surgical treatment Case Age /Sex Seizure type 1 2 m/m GTS with Rt. F-T area head drop Diffuse bilateral slow spike and wave 2 6 m/m IS LGS Multifocal spike discharges (O2, O1, C4, T4) and generalized epileptiform discharges 3 15 m/f IS, Drop attack Interictal EEG Ictal EEG Brain MRI Surgery Outcome Generalized epileptiform discharges, Rt. P-O areas and Lt. C area 4 57 m/m CPS Focal slowings and spike from Lt. T-P areas Diffuse generalized spike and slow wave and fast activities Fast activities from Rt. F-C area generalized spike and slow wave discharges Generalized slowings theta slowings over Rt. C-P-T area Cortical dysplasia in Rt. F lobe Multiple SEN and cortical tubers Rt. P large tuber Rt. T-P delta Multiple calcified Lt. hemispheric nodules in Lt. T spike, Lt. side delta and O lobe Lt. hemispheric spike Age: 20 m Ant. F lesionectomy Age: 28 m 70~80% Rt. F corticectomy + seizure T tuberectomy + reduction callosotomy aggravation Age: 22 m Rt. P lesionectomy Age: 58 m Lt. T lobectomy Recurred after 4 years Postop. F/U M, male; F, female; m, months; IS, infantile spasms; LGS, Lennox-Gastaut Syndrome; GTS, generalized tonic seizure; CPS, complex partial seizure; EEG, electroencephalography; MRI, magnetoencephalography; F, frontal; C, central; T, temporal; P, parietal; O, occipital; SEN, subependymal nodule; F/U, follow-up. 52 m 25 m 23 m 106 m 62
증등의발생과연관이있기때문에 vigabatrin 의우수한항경련효과는더욱중요한의미를가진다. 17,18 Jambaque 등 19 은결절성경화증과영아연축이동반된환자들중 vigabatrin을투여하여발작이조절되었던환자들에서유의하게인지와행동이호전되었다고보고하면서조기에영아연축을조절하여이차적전신화를차단하는것이결절성경화증환자의정신발달에중요하다는점을강조하였다. 결절성경화증에서간질수술의적응증은병변이단일결절이거나, 여러개의병변이있더라도수술전검사를통해발작의원인이되는병변을국소화할수있어야한다. 20-24 문헌고찰에따르면, 결절성경화증으로간질수술을받은 177 예중 57% 인 101예에서발작이소실되었으며 90% 의환자에서발작의빈도가감소하였다. 25 Lachhwani 등 24 의연구에서는뇌자기공명영상과뇌파소견이일치한환자에서 89% 에서경련발작이소실되었으나, 그렇지않은환자에서는 38% 의발작소실률을보였다. 국내보고로는정등 26 이결절성경화증에서의난치성간질 3예에서수술적치료에대해보고한바있다. 단일병변 1예와다발성병변 2예에서수술전검사로경련을유발한병변에대한국소화가가능하였으며수술후 3예모두에서발작이소실되었다고보고하였으나, 수술후추적관찰기간이 5개월, 12개월, 16개월밖에되지않았기때문에좀더장기간에걸친추적관찰이필요하다고생각된다. 본연구에서는 4예에서간질수술이시행되어 2예에서발작이소실되었는데, 앞서기술한바와같이뇌자기공명영상과뇌파에서간질유발성병변이확실하게국소화되었던환자들에서수술후예후가좋았다. 그러나최근에는명백한국소화가되지않아도다양한수술전검사의발달로상황에따라서는다병변절제나다단계절제등좀더적극적인수술방법이이용될수있으며, 이러한적극적인치료를통해난치성간질을가진결절성경화증환아의인지기능, 행동발달및전반적인삶의질을향상시킬수있다는주장도제기되고있다. 27 결론적으로본연구에서소아결절성경화증환자에서간질의유병률은 77.0% 였으며 29.8% 인 17예에서시간에따른발작유형의변화가관찰되었다. 약물치료및수술적치료로반수에서발작이비교적잘조절되었으며영아연축에서 vigabatrin의효과가우수한경향을보였다. 본연구에서는영아연축동반여부와발작의발병연령, 발작형태의변화에따른발작의소실률에서의미있는차이는없었으며, 예후인자에대해서는좀더장기간추적관찰이필요할것으로생각된다. REFERENCES 1. Curatolo P. Tuberous sclerosis: relationships between clinical and EEG findings and magnetic resonance imaging. Dysplasias of cerebral cortex and epilepsy. 1 st ed. Philadelphia: Lippincott-Raven. p. 1996:191-8. 2. Curatolo P, Bombardieri R, Cerminara C. Current management for epilepsy in tuberous sclerosis complex. Curr Opin Neurol 2006;19: 119-23. 3. Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet 2008;372:657-68. 4. Curatolo P, Verdecchia M, Bombardieri R. Tuberous sclerosis complex: a review of neurological aspects. Eur J Paediatr Neurol 2002; 6:15-23. 5. Gomez MR, Sampson JR, Whittemore VH. Tuberous sclerosis complex. 3 rd ed. Oxford University Press New York; 1999. 6. Koh S, Jayakar P, Dunoyer C, et al. Epilepsy surgery in children with tuberous sclerosis complex: presurgical evaluation and outcome. Epilepsia 2000;41:1206-13. 7. Edwards JC, Wyllie E, Ruggeri PM, et al. Seizure outcome after surgery for epilepsy due to malformation of cortical development. Neurology 2000;55:1110-4. 8. Roach ES, Smith M, Huttenlocher P, Bhat M, Alcorn D, Hawley L. Diagnostic criteria: tuberous sclerosis complex. Report of the Diagnostic Criteria Committee of the National Tuberous Sclerosis Association. J Child Neurol 1992;7:221-4. 9. Ki Joong Kim, Yong Seung Hwang. Features and outcomes of epileptic seizure in tuberous sclerosis. J Korean Child Nerol Soc 1995; 2:93-8. 10. Ohtsuka Y, Ohmori I, Oka E. Long-term follow-up of childhood epilepsy associated with tuberous sclerosis. Epilepsia 1998;39:1158-63. 11. Curatolo P, Seri S, Verdecchia M, Bombardieri R. Infantile spasms in tuberous sclerosis complex. Brain Dev 2001;23:502-7. 12. Muzykewicz DA, Costello DJ, Halpern EF, Thiele EA. Infantile spasms in tuberous sclerosis complex: Prognostic utility of EEG. Epilepsia 2009;50:290-6. 13. Aicardi J, Mumford JP, Dumas C, Wood S. Vigabatrin as initial therapy for infantile spasms: a European retrospective survey. Sabril IS Investigator and Peer Review Groups. Epilepsia 1996;37:638-42. 14. Chiron C, Dulac O, Luna D, et al. Vigabatrin in infantile spasms. Lancet 1990;335:363. 15. Chiron C, Dumas C, Jambaque I, Mumford J, Dulac O. Randomized trial comparing vigabatrin and hydrocortisone in infantile spasms due to tuberous sclerosis1. Epilepsy Res 1997;26:389-95. 16. Hancock E, Osborne JP. Topical Review: Vigabatrin in the treatment of infantile spasms in tuberous sclerosis: literature review. J Child Neurol 1999;14:71-4. 17. Bolton PF, Griffiths PD. Association of tuberous sclerosis of temporal lobes with autism and atypical autism. Lancet 1997;349:392-5. 18. Riikonen R, Amnell G. Psychiatric disorders in children with earlier infantile spasms. Dev Med Child Neurol 1981;23:747-60. 19. Jambaque I, Chiron C, Dumas C, Mumford J, Dulac O. Mental and behavioural outcome of infantile epilepsy treated by vigabatrin in tuberous sclerosis patients. Epilepsy Res 2000;38:151-60. Journal of Korean Epilepsy Society Vol. 13 No. 2, 2009 63
20. Avellino AM, Berger MS, Rostomily RC, Shaw CM, Ojemann GA. Surgical management and seizure outcome in patients with tuberous sclerosis. J Neurosurg 1997;87:391-6. 21. Chandra PS, Salamon N, Huang J, et al. FDG-PET/MRI coregistration and diffusion-tensor imaging distinguish epileptogenic tubers and cortex in patients with tuberous sclerosis complex: a preliminary report. Epilepsia 2006;47:1543-9. 22. Jarrar RG, Buchhalter JR, Raffel C. Long-term outcome of epilepsy surgery in patients with tuberous sclerosis. Neurology 2004;62: 479-81. 23. Karenfort M, Kruse B, Freitag H, Pannek H, Tuxhorn I. Epilepsy surgery outcome in children with focal epilepsy due to tuberous sclerosis complex. Neuropediatrics 2002;33:255-61. 24. Lachhwani DK, Pestana E, Gupta A, Kotagal P, Bingaman W, Wyllie E. Identification of candidates for epilepsy surgery in patients with tuberous sclerosis. Neurology 2005;64:1651-4. 25. Jansen FE, van Huffelen AC, Algra A, van Nieuwenhuizen O. Epilepsy surgery in tuberous sclerosis: a systematic review. Epilepsia 2007;48:1477-84. 26. Da Eun Jung, Jung Chae Park, Hee Jung Chung, Hoon Chul Kang, Heung Dong Kim, Yong Soon Hwang. The cases of surgical treatment of intractable childhood epielpsy with tuberous sclerosis. J Korean Child Nerol Soc 2002;10:314-24. 27. Romanelli P, Najjar S, Weiner HL, Devinsky O. Epilepsy surgery in tuberous sclerosis: multistage procedures with bilateral or multilobar foci. J Child Neurol 2002; 17: 689-92. 64